Diabetes Medication - General
A signal of increased lower limb amputation (primarily of the toe) in people taking canagliflozin compared with placebo in a clinical trial in high cardiovascular risk patients is currently under investigation.
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated in adults with type 2 diabetes mellitus to improve glycaemic control when diet and exercise alone do not provide adequate glycaemic control. Canagliflozin is given as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.
Canagliflozin can also be given as add-on therapy with other glucose-lowering drugs, including insulin, when these do not provide adequate glycaemic control.
The canagliflozin-containing medicines marketed in the UK areInvokana▼(canagliflozin) and Vokanamet▼ (canagliflozin and metformin).
The incidence of lower limb amputation (primarily of the toe) is higher in the canagliflozin groups compared with the placebo group in a clinical trial of high cardiovascular risk patients (CANVAS, an on-going long-term cardiovascular outcomes trial). The trial is fully enrolled with 4,330 randomised participants. The mean and median follow-up time is approximately 4.5 years.
The incidence of lower limb amputation is 7 per 1000 patient-years in the canagliflozin 100 mg group and 5 per 1000 patient-years in the canagliflozin 300 mg group, compared with 3 per 1000 patient-years in the placebo group.
This increased risk was observed independent of risk factors. However, the absolute risk was higher in patients with previous amputations, existing peripheral vascular disease, or neuropathy. No dose response was observed.
Any possible mechanism behind these events is as yet unknown. However, dehydration and volume depletion might increase this risk. We therefore recommend that you follow the interim advice outlined above while this signal is being investigated by the European Medicines Agency. The results of the review will be communicated when available.
Other trials: no significantly increased risk observedIn an ongoing outcome trial with a similar population to CANVAS, theCANVAS-R trial, there have been 16 amputations in the canagliflozin group and 12 amputations in the placebo group. The estimated annualised incidence of amputations is 7 per 1000 patient-years in the canagliflozin group compared with 5 per 1000 patient-years in the placebo group (no statistically significant difference).
12 completed phase 3 or 4 trials have shown no increase in amputation incidence with canagliflozin (incidence of 0.6 per 1000 patient-years in canagliflozin groups and 2 per 1000 patient-years in control groups; mean follow-up of 0.9 years).
Source : MHRA Gov UK (June 2016)
FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR)
The U.S. Food and Drug Administration (FDA) has strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports, we have revised the warnings in the drug labels to include information about acute kidney injury and added recommendations to minimize this risk.
Patients should seek medical attention immediately if they experience signs and symptoms of acute kidney injury. This is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body. Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet. Patients should not stop taking their medicine without first talking to their health care professionals. Doing so can lead to uncontrolled blood sugar levels that can be harmful.
Health care professionals should consider factors that may predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin. These include decreased blood volume; chronic kidney insufficiency; congestive heart failure; and taking other medications such as diuretics, blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Assess kidney function prior to starting canagliflozin or dapagliflozin and monitor periodically thereafter. If acute kidney injury occurs, promptly discontinue the drug and treat the kidney impairment.
Canagliflozin and dapagliflozin are prescription medicines used with diet and exercise to help lower blood sugar in adults with type 2 diabetes. They belong to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin and dapagliflozin lower blood sugar by causing the kidneys to remove sugar from the body through the urine. Untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease.
From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases* of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use (see Data Summary). This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware. In approximately half of the cases, the events of acute kidney injury occurred within 1 month of starting the drug, and most patients improved after stopping it. Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low blood pressure, or were taking other medicines that can affect the kidneys.
Source : FDA (June 2016)
FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density
FDA has strengthened the warning for the type 2 diabetes medicine canagliflozin (Invokana, Invokamet) related to the increased risk of bone fractures, and added new information about decreased bone mineral density. To address these safety concerns, FDA added a new Warning and Precaution and revised the Adverse Reactions section of the Invokana and Invokamet drug labels.
FDA is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class, including dapagliflozin (Farxiga, Xigduo XR) and empaglifozin (Jardiance, Glyxambi, Synjardy), to determine if additional label changes or studies are needed. Health care professionals and patients are urged to report side effects involving canagliflozin or other SGLT2 inhibitors to the FDA MedWatch program.
BACKGROUND: Canagliflozin is a prescription medicine used with diet and exercise to lower blood sugar in adults with type 2 diabetes. It belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin is available as a single-ingredient product under the brand name Invokana and also in combination with the diabetes medicine metformin under the brand name Invokamet. Bone mineral density relates to the strength of a person’s bones.
RECOMMENDATIONS: Health care professionals should consider factors that contribute to fracture risk prior to starting patients on canagliflozin. Patients should talk to their health care professionals about factors that may increase their risk for bone fracture. Patients should not stop or change their diabetes medicines without first talking to their health care professional. Additional information for Health Care Professionals:
- Bone fractures have been seen in patients taking the type 2 diabetes medicine canagliflozin.
- Fractures can occur as early as 12 weeks after starting canagliflozin.
- Canagliflozin has also been linked to decreases in bone mineral density at the hip and lower spine.
- Consider factors that contribute to fracture risk prior to initiating canagliflozin.
- Counsel patients about factors that may contribute to bone fracture risk.
Do not stop or change your diabetes medicines without first talking to your health care professional. When untreated, diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease.
Source : FDA (Sept 2015)
DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain
ISSUE: The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. FDA has added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, called dipeptidyl peptidase-4 (DPP-4) inhibitors. See the Drug Safety Communication for a complete list of all FDA-approved DPP-4 inhibitors.
BACKGROUND: DPP-4 inhibitors are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. When untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. These medicines are available as single-ingredient products and in combination with other diabetes medicines such as metformin.
RECOMMENDATION: Patients should not stop taking their DPP-4 inhibitor medicine, but should contact their health care professional right away if they experience severe and persistent joint pain. Health care professionals should consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue the drug if appropriate.
Source : FDA (Aug 2015)
FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood
The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization. We are continuing to investigate this safety issue and will determine whether changes are needed in the prescribing information for this class of drugs, called sodium-glucose cotransporter-2 (SGLT2) inhibitors.
Patients should pay close attention for any signs of ketoacidosis and seek medical attention immediately if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. Do not stop or change your diabetes medicines without first talking to your prescriber. Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis and monitor sugar levels.
SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. When untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. These medicines are available as single-ingredient products and also in combination with other diabetes medicines such as metformin (see Table 1 below). The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.
A search of the FDA Adverse Event Reporting System (FAERS) database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014 (see Data Summary). All patients required emergency room visits or hospitalization to treat the ketoacidosis. Since June 2014, we have continued to receive additional FAERS reports for DKA and ketoacidosis in patients treated with SGLT2 inhibitors.
DKA, a subset of ketoacidosis or ketosis in diabetic patients, is a type of acidosis that usually develops when insulin levels are too low or during prolonged fasting. DKA most commonly occurs in patients with type 1 diabetes and is usually accompanied by high blood sugar levels. The FAERS cases were not typical for DKA because most of the patients had type 2 diabetes and their blood sugar levels, when reported, were only slightly increased compared to typical cases of DKA. Factors identified in some reports as having potentially triggered the ketoacidosis included major illness, reduced food and fluid intake, and reduced insulin dose.
We urge health care professionals and patients to report side effects involving SGLT2 inhibitors to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
Table 1. List of SGLT2 inhibitors
Brand name Active ingredient(s)
Invokamet canagliflozin and metformin
Xigduo XR dapagliflozin and metformin extended-release
Glyxambie mpagliflozin and linagliptin
Source : FDA (May 2015)
Heart risks of glucose-lowering drugs being overlooked in clinical trials
Why is heart failure not more rigorously assessed in clinical trials of antidiabetes drugs? In a Personal View, published in The Lancet Diabetes & Endocrinology journal, Professor John McMurray of The University of Glasgow and colleagues review evidence that hospitalization for heart failure is one of the most common and prognostically important complications of diabetes. Moreover, increasing evidence shows that some glucose-lowering drugs increase the risk of heart failure. Yet, heart failure is rarely considered as a key outcome, or even part of composite cardiovascular outcomes, in clinical trials of glucose-lowering drugs.
Previously, the ability of an antidiabetes drug to lower glucose was used in clinical trials accepted as a surrogate of its ability to reduce the risk of microvascular disease, and possibly cardiovascular risk. Recent evidence has suggested, however, that some antidiabetes drugs may increase patients' cardiovascular risk, despite their ability to effectively lower blood glucose. These findings have prompted the FDA and EMA to make new regulations requiring cardiovascular outcomes trials for new antidiabetes drugs.
Such cardiovascular outcomes trials have typically used so-called major adverse cardiovascular events (MACE) as a primary outcome. This combined outcome usually includes cardiovascular death, heart attack, and stroke. However, as McMurray and colleagues explain, heart failure can be more common than any of these other cardiovascular outcomes, especially in patients with advanced diabetes, and it is also more closely associated with premature death. Thus, its omission as a key endpoint in clinical trials could mean that important cardiovascular effects of the glucose-lowering drugs being tested are being overlooked.
According to Professor McMurray, "Fortunately, some trials in progress are taking heart failure into account as a secondary outcome. But many others are neglecting to report this important complication as a key trial outcome. Until heart failure is systematically evaluated in clinical trials, the cardiovascular safety of antidiabetes drugs will remain uncertain."
Explore further: Common diabetes drug fails to fulfill promise of improving cardiovascular risk in people without diabetes
More information: Study paper: www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70031-2/abstract
Source : Medical Xpress (March 2014)